Sibutramine

Treatment should consist of general measures employed in the management of overdosage: an airway should be established as needed; cardiac and vital sign monitoring is recommended; general symptomatic and supportive measures should be instituted. Cautious use of p-blockers may be indicated to control elevated blood pressure or tachycardia. (L1712)

In a double-blind, placebo-controlled, crossover study in 19 volunteers, administration of a single dose of ethanol (0.5 mL/kg) together with 20 mg of sibutramine resulted in no psychomotor interactions of clinical significance between alcohol and sibutramine. However, the concomitant use of Meridia and excess alcohol is not recommended.

The rare, but serious, constellation of symptoms termed "serotonin syndrome" has also been reported with the concomitant use of selective serotonin reuptake inhibitors and agents for migraine therapy, such as Imitrex (sumatriptan succinate) and dihydroergotamine, certain opioids, such as dextromethorphan, meperidine, pentazocine and fentanyl, lithium, or tryptophan. Serotonin syndrome has also been reported with the concomitant use of two serotonin reuptake inhibitors. The syndrome requires immediate medical attention and may include one or more of the following symptoms: excitement, hypomania, restlessness, loss of consciousness, confusion, disorientation, anxiety, agitation, motor weakness, myoclonus, tremor, hemiballismus, hyperreflexia, ataxia, dysarthria, incoordination, hyperthermia, shivering, pupillary dilation, diaphoresis, emesis, and tachycardia. Because sibutramine inhibits serotonin reuptake, in general, it should not be administered with other serotonergic agents ... . However, if such a combination is clinically indicated, appropriate observation of the patient is warranted

Potential pharmacologic interaction when sibutramine is used with monoamine oxidase (MAO) inhibitors (e.g., phenelzine, selegiline). Serotonin syndrome, potentially serious or fatal.Concomitant use contraindicated; discontinue MAO inhibitors at least 2 weeks before starting sibutramine or discontinue sibutramine at least 2 weeks before starting MAO inhibitors.

Concomitant use of Meridia and other agents that may raise blood pressure or heart rate have not been evaluated. These include certain decongestants, cough, cold, and allergy medications that contain agents such as ephedrine, or pseudoephedrine. Caution should be used when prescribing Meridia to patients who use these medications.

For more Interactions (Complete) data for SIBUTRAMINE (6 total), please visit the HSDB record page.

Using large amounts of these drugs can result in a condition known as amphetamine psychosis -- which can result in auditory, visual and tactile hallucinations, intense paranoia, irrational thoughts and beliefs, delusions, and mental confusion.

Sibutramine has not been linked to an increased rate of serum enzyme elevations during therapy, but the results of serum ALT monitoring have been reported only rarely. Despite its long term availability, only a single case report of acute liver injury attributed to sibutramine has been published. The time to onset was 2 weeks and the pattern of liver enzyme elevation was cholestatic. The liver injury was anicteric and self-limited in course (Case 1). Immunoallergic and autoimmune features were absent. There have been no reports of acute liver failure or chronic liver injury attributed to sibutramine.

Sibutramine produces its therapeutic effects by inhibition of norepinephrine (NE), serotonin (5-hydroxytryptamine, 5-HT), and to a lesser extent, dopamine reuptake at the neuronal synapse. By inhibiting the reuptake of these neurotransmitters, sibutramine promotes a sense of satiety and decrease in appetite, thereby reducing food intake. Data from animal studies also suggest that sibutramine may also increase energy expenditure through thermogenic effects in both the basal and fed states, but this has not been confirmed in humans. Sibutramine and its major pharmacologically active metabolites (M1 and M2) do not act via release of monoamines.

/SIGNS AND SYMPTOMS/ There is limited experience of overdose with sibutramine. The most frequently noted adverse events associated with overdose are tachycardia, hypertension, headache and dizziness.

/CASE REPORTS/ Sibutramine, a serotonin reuptake inhibitor, currently is used in treatment of obesity. The known side effects of sibutramine, ie, hypertension and tachycardia, depend on its adrenergic and serotoninergic effects. ... A case of life-threatening hyponatremia associated with sibutramine use in an obese woman /is described/. /It was/ hypothesize that sibutramine, through its effect on neurotransmitters, may induce antidiuretic hormone secretion and lead to a syndrome of inappropriate antidiuretic hormone secretion. We advise careful monitoring of water-electrolytic balance during sibutramine therapy.

/CASE REPORTS/ Post-marketing surveillance using prescription event monitoring in the New Zealand Intensive Medicines Monitoring Programme (IMMP) identified a case of QT prolongation and associated cardiac arrest in a patient taking sibutramine for 25 days. This patient was further investigated, including genotyping for long QT syndrome. Other IMMP case reports suggesting arrhythmias associated with sibutramine were assessed and further reports were obtained from the World Health Organisation (WHO) adverse drug reactions database. The index case displayed a novel mutation in a cardiac potassium channel subunit gene, KCNQ1, which is likely to prolong cardiac membrane depolarization and increase susceptibility to long QT intervals. Assessment of further IMMP reports identified five additional patients who experienced palpitations associated with syncope or presyncopal symptoms, one of whom had a QT(c) at the upper limit of normal. Assessment of reports from the WHO database identified three reports of QT prolongation and one fatal case of torsade de pointes in a patient also taking cisapride. This case series suggests that sibutramine may be associated with QT prolongation and related dysrhythmias. ...

/CASE REPORTS/ A previously well 51-year-old woman with obesity but no other relevant past medical history or cardiac risk factors was prescribed sibutramine (initial dose 10 mg daily, increased to 15 mg daily after 10 wk). Four months after initiation of therapy, the woman developed ventricular fibrillation and was successfully resuscitated. On admission, an electrocardiogram (ECG) demonstrated sinus tachycardia without any ischemic changes and a prolonged QTc interval (545 msec). A subsequent coronary angiogram revealed normal coronary arteries and no other abnormalities. Her QTc interval returned to normal (432 msec) by day 2 and remained within normal limits (<440 msec) thereafter. Due to a favorable neurologic recovery and the absence of any cardiac structural abnormality, the patient was readmitted for implantation of an automatic implantable cardioverter-defibrillator on day 35 and remained well from a cardiac and neurologic standpoint at a 2-year follow-up examination. Sibutramine acts centrally to inhibit noradrenaline, dopamine, and serotonin reuptake, thereby sharing similar actions of other QT interval-prolonging drugs. Therefore, sibutramine might be anticipated to also share a tendency to QT interval prolongation.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

sibutramine

DILI Positive

Oral

DOI:10.1016/j.drudis.2019.09.022

/LABORATORY ANIMALS: Acute Exposure/ Sibutramine is a serotonin and norepinephrine reuptake inhibitor, used in the treatment of obesity. In this study, cardiovascular effects of sibutramine (0.9, 3, or 9 mg kg(-1) i.p.) were measured in conscious Sprague-Dawley rats, in the absence and presence of beta- and/or alpha-adrenoceptor antagonism (with propranolol and/or phentolamine, respectively). Sibutramine caused pressor and tachycardic effects, with celiac and mesenteric vasoconstrictions, and hyperemic hindquarters vasodilatation. Pretreatment with propranolol inhibited the tachycardic and hindquarters vasodilator effect of sibutramine, whereas phentolamine inhibited the pressor and vasoconstrictor effects of sibutramine. In the presence of phentolamine, sibutramine caused hyperemic mesenteric vasodilatation. In preconstricted, isolated, mesenteric vessels, sibutramine and its metabolites BTS 54505 (N-desmethylsibutramine) and BTS 54354 (N-didesmethylsibutramine) (10 microM) produced significant vasodilations. Neither sibutramine nor BTS 54505 enhanced vessel sensitivity to norepinephrine, whereas BTS 54 354 produced a significant leftward shift in the concentration-response curve to norepinephrine. Collectively, the results indicate that the overt cardiovascular effects of sibutramine involve alpha-adrenoceptor-mediated celiac and mesenteric vasoconstrictions, and beta-adrenoceptor-mediated hindquarters vasodilatation and tachycardia. The mesenteric vasodilator response to sibutramine, seen in the presence of phentolamine, may be a direct effect of the drug and/or its metabolites, on vessel tone. The cardiovascular effects of sibutramine in vivo may be secondary to inhibition of peripheral and/or central reuptake of monoamines by the metabolites BTS 54354 and/or BTS 54505. It remains to explain why BTS 54354, but not BTS 54505, enhanced norepinephrine sensitivity in vitro, because both metabolites are potent inhibitors of the norepinephrine transporter.

/LABORATORY ANIMALS: Acute Exposure/ Sibutramine is an inhibitor of norepinephrine and 5-HT reuptake largely used in the management of obesity. ... Postmarketing adverse effects of sibutramine were reported including abnormal ejaculation in men. This study investigates the effects of sibutramine on ejaculation and vas deferens and seminal vesicle contractility. Adult male rats received sibutramine (5; 20; or 50 mg kg(-1), ip) and after 60 min were exposed to receptive females for determination of ejaculation parameters. The vasa deferentia and seminal vesicles of untreated rats were mounted in isolated organ baths for recording of isometric contractions and HEK293 cells loaded with fluorescent calcium indicator were used to measure intracellular Ca(2+) transients. Sibutramine 5 and 20 mg kg(-1) reduced ejaculation latency whereas 50 mg kg(-1) increased ejaculation latency. Sibutramine 3 to 30 uM greatly increased the sensitivity of the seminal vesicle and vas deferens to norepinephrine, but at concentrations higher than 10 uM there were striking depressions of maximal contractions induced by norepinephrine, carbachol and CaCl(2). In HEK293 cells, sibutramine 10 to 100 uM inhibited intracellular Ca(2+) transients induced by carbachol. Depending on the doses, sibutramine either facilitates or inhibits ejaculation. Apart from its actions in the central nervous system, facilitation of ejaculation may result from augmented sensitivity of smooth muscles to norepinephrine while reductions of intracellular Ca(2+) may be involved in the delayed ejaculation observed with high doses of sibutramine.

Sibutramine should not be used in patients with severe renal impairment, including those with end-stage renal disease undergoing dialysis. Use with caution in patients with mild or moderate renal impairment.

/Sibutramine/ ... should not be used in patients with severe hepatic impairment.

Experience with sibutramine in patients 65 years of age and older is insufficient to determine whether they respond differently than younger adults; sibutramine is contraindicated in geriatric patients older than 65 years of age.

Meridia is contraindicated in patients who have a major eating disorder (anorexia nervosa or bulimia nervosa)..

Because Meridia can cause mydriasis, it should be used with caution in patients with narrow angle glaucoma.

Schedule IV shall consist of the drugs and other substances, by whatever official name, common or usual name, chemical name, or brand name designated, listed in this section. Each drug or substance has been assigned the DEA Controlled Substances Code Number set forth opposite it. Stimulants: Unless specifically excepted or unless listed in another schedule, any material, compound, mixture, or preparation which contains any quantity of the following substances having a stimulant effect on the central nervous system, including its salts, isomers and salts of isomers: Sibutramine (DEA Code Number: 1675) is included on this list.

MEDICATION

Use (kg; approx.) in Germany (2009): >75

For the treatment of obesity.

Sibutramine is no longer available in the U.S. (revision date: 10/01/2010)

/Schedule IV/ controlled substance (stimulant)